This proposal is the second revision of our competing renewal of our previous R01 studying dopamine pathology in schizophrenia. Based on the results of those studies we have turned our interest to the anatomical and neurochemical basis of treatment response or resistance. The typical symptoms of schizophrenia are psychosis, cognitive impairments and negative symptoms, and the treatment available is based in the use of antipsychotic medications, which primarily act blocking dopamine receptors in some degree. Unfortunately, not all patients respond to treatment, and in those who do, only psychotic symptoms are usually improved. In fact, approximately 30% of patients do not respond to these treatments at all, and are considered treatment-non-responders or treatment resistant. This clearly points out the need of finding the basis of these differences in treatment response in order to develop new therapies. The basis of these differences are currently unknown but some lines of evidence (including work performed by our group), point towards different dopamine anomalies ('dopamine phenotypes) in treatment-responders vs treatment-non- responders (Abi-Dargham et al, 2000; Roberts et al, 2009). The overall goal of this proposal is to identify components of the dopaminergic transmission that may underlie the existence of different dopamine phenotypes in treatment-responders vs treatment-non- responders. We propose a multitier approach to analyze dopamine pathologies in postmortem substantia nigra-ventral tegmental area (SN/VTA), [the area of the brain that houses the majority of the dopaminergic cells], in schizophrenia treatment-responders vs treatment-non-responders, comparing also with healthy controls. We will test the capability of these dopamine neurons to produce dopamine, the health of the dopamine cell populations, and the modulation of these cells by the glutamatergic system, all with the common goal of identifying specific anomalies that can be linked to success/failure in treatment response. Even when dopamine has a central role in schizophrenia pathology, there are very scarce studies on anomalies of the SN/VTA in schizophrenia, and even rarer is the study of treatment response in postmortem human brain, both facts making our project unique. More importantly, finding neuroanatomical and neurochemical biomarkers of treatment response should allow the identification of potential targets for the development of new and more specific therapies, as well as provide a framework for the development of neuroimaging tools aimed to the prediction of treatment response outcomes. PUBLIC HEALTH RELEVANCE: Identifying the neuroanatomical and neurochemical substrates underlying treatment response/resistance to the currently available antipsychotic medications in schizophrenia should provide new potential targets for treatment intervention, as well as a framework to develop tools for the prediction of treatment outcomes.